Hormonal control of androgen receptor function through SIRT1

Mol Cell Biol. 2006 Nov;26(21):8122-35. doi: 10.1128/MCB.00289-06. Epub 2006 Aug 21.

Abstract

The NAD-dependent histone deacetylase Sir2 plays a key role in connecting cellular metabolism with gene silencing and aging. The androgen receptor (AR) is a ligand-regulated modular nuclear receptor governing prostate cancer cellular proliferation, differentiation, and apoptosis in response to androgens, including dihydrotestosterone (DHT). Here, SIRT1 antagonists induce endogenous AR expression and enhance DHT-mediated AR expression. SIRT1 binds and deacetylates the AR at a conserved lysine motif. Human SIRT1 (hSIRT1) repression of DHT-induced AR signaling requires the NAD-dependent catalytic function of hSIRT1 and the AR lysine residues deacetylated by SIRT1. SIRT1 inhibited coactivator-induced interactions between the AR amino and carboxyl termini. DHT-induced prostate cancer cellular contact-independent growth is also blocked by SIRT1, providing a direct functional link between the AR, which is a critical determinant of progression of human prostate cancer, and the sirtuins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Amino Acid Sequence
  • Animals
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cell Proliferation
  • Dihydrotestosterone / metabolism*
  • Gene Expression Regulation*
  • Genes, Reporter
  • Histone Acetyltransferases / metabolism
  • Humans
  • Lysine / metabolism
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Peptides / genetics
  • Peptides / metabolism
  • Prostatic Neoplasms*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Signal Transduction / physiology
  • Sirtuin 1
  • Sirtuins / genetics
  • Sirtuins / metabolism*
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • p300-CBP Transcription Factors

Substances

  • Cell Cycle Proteins
  • Peptides
  • Receptors, Androgen
  • Transcription Factors
  • Dihydrotestosterone
  • Histone Acetyltransferases
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • SIRT1 protein, human
  • Sirtuin 1
  • Sirtuins
  • Lysine